Ferroptosis Regulator Information

General Information of the Ferroptosis Regulator (ID: REG10170)
Regulator Name Ubiquitin carboxyl-terminal hydrolase 11 (USP11)
Synonyms
UHX1; Deubiquitinating enzyme 11; Ubiquitin thioesterase 11; Ubiquitin-specific-processing protease 11
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Gene Name USP11
Gene ID 8237
Regulator Type Protein coding
Uniprot ID P51784
Sequence
MAVAPRLFGGLCFRFRDQNPEVAVEGRLPISHSCVGCRRERTAMATVAANPAAAAAAVAA
AAAVTEDREPQHEELPGLDSQWRQIENGESGRERPLRAGESWFLVEKHWYKQWEAYVQGG
DQDSSTFPGCINNATLFQDEINWRLKEGLVEGEDYVLLPAAAWHYLVSWYGLEHGQPPIE
RKVIELPNIQKVEVYPVELLLVRHNDLGKSHTVQFSHTDSIGLVLRTARERFLVEPQEDT
RLWAKNSEGSLDRLYDTHITVLDAALETGQLIIMETRKKDGTWPSAQLHVMNNNMSEEDE
DFKGQPGICGLTNLGNTCFMNSALQCLSNVPQLTEYFLNNCYLEELNFRNPLGMKGEIAE
AYADLVKQAWSGHHRSIVPHVFKNKVGHFASQFLGYQQHDSQELLSFLLDGLHEDLNRVK
KKEYVELCDAAGRPDQEVAQEAWQNHKRRNDSVIVDTFHGLFKSTLVCPDCGNVSVTFDP
FCYLSVPLPISHKRVLEVFFIPMDPRRKPEQHRLVVPKKGKISDLCVALSKHTGISPERM
MVADVFSHRFYKLYQLEEPLSSILDRDDIFVYEVSGRIEAIEGSREDIVVPVYLRERTPA
RDYNNSYYGLMLFGHPLLVSVPRDRFTWEGLYNVLMYRLSRYVTKPNSDDEDDGDEKEDD
EEDKDDVPGPSTGGSLRDPEPEQAGPSSGVTNRCPFLLDNCLGTSQWPPRRRRKQLFTLQ
TVNSNGTSDRTTSPEEVHAQPYIAIDWEPEMKKRYYDEVEAEGYVKHDCVGYVMKKAPVR
LQECIELFTTVETLEKENPWYCPSCKQHQLATKKLDLWMLPEILIIHLKRFSYTKFSREK
LDTLVEFPIRDLDFSEFVIQPQNESNPELYKYDLIAVSNHYGGMRDGHYTTFACNKDSGQ
WHYFDDNSVSPVNENQIESKAAYVLFYQRQDVARRLLSPAGSSGAPASPACSSPPSSEFM
DVN

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Family Peptidase C19 family
Function
Protease that can remove conjugated ubiquitin from target proteins and polyubiquitin chains. Inhibits the degradation of target proteins by the proteasome. Cleaves preferentially 'Lys-6' and 'Lys- 63'-linked ubiquitin chains. Has lower activity with 'Lys-11' and 'Lys- 33'-linked ubiquitin chains, and extremely low activity with 'Lys-27', 'Lys-29' and 'Lys-48'-linked ubiquitin chains (in vitro). Plays a role in the regulation of pathways leading to NF-kappa-B activation. Plays a role in the regulation of DNA repair after double-stranded DNA breaks. Acts as a chromatin regulator via its association with the Polycomb group (PcG) multiprotein PRC1-like complex; may act by deubiquitinating components of the PRC1-like complex. Promotes cell proliferation by deubiquitinating phosphorylated E2F1.

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HGNC ID
HGNC:12609
KEGG ID hsa:8237
Full List of the Ferroptosis Target of This Regulator and Corresponding Disease/Drug Response(s)
USP11 can regulate the following target(s), and cause disease/drug response(s). You can browse detail information of target(s) or disease/drug response(s).
Browse Target
Browse Disease
Browse Drug
Nuclear factor erythroid 2-related factor 2 (NFE2L2) [Suppressor; Marker]
 Target Info 
In total 2 item(s) under this target
Experiment 1 Reporting the Ferroptosis Target of This Regulator [1]
Target for Ferroptosis Marker/Suppressor
Responsed Disease Lung cancer ICD-11: 2C25
 Disease Info 
Responsed Drug RSL3 Investigative
 Drug Info 
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Ubiquitin mediated proteolysis hsa04120
Cell Process Cell ferroptosis
In Vitro Model
 A-549 cells Lung adenocarcinoma Homo sapiens CVCL_0023
H2122 cells Lung adenocarcinoma Homo sapiens CVCL_1531
In Vivo Model
After two weeks in house, the mice were subcutaneously injected with A549 cells (100 uL containing 5 x 106 cells/injection) and monitored for tumor cell xenografts to reach approximately 100 mm3. The mice were then divided into two groups (n = 5), the RSL3 treatment (100 mg/kg; dissolved in 5% dimethyl sulfoxide/corn oil; administrated intratumorally twice a day for one week) and control (5% dimethyl sulfoxide/corn oil only) groups.

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Response regulation RSL3 was able to directly bind to USP11, a recently identified de-ubiquitinase of NRF2, and inactivate USP11 protein to induce NRF2 protein ubiquitination and degradation in KLK lung adenocarcinoma cells.
Experiment 2 Reporting the Ferroptosis Target of This Regulator [2]
Target for Ferroptosis Marker/Suppressor
Responsed Disease Lung cancer ICD-11: 2C25
 Disease Info 
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Ubiquitin mediated proteolysis hsa04120
Cell Process Cell ferroptosis
Cell proliferation
In Vitro Model
 HEK-293T cells Normal Homo sapiens CVCL_0063
NCI-H1299 cells Lung large cell carcinoma Homo sapiens CVCL_0060
HCT 116 cells Colon carcinoma Homo sapiens CVCL_0291
A-549 cells Lung adenocarcinoma Homo sapiens CVCL_0023
HeLa cells Endocervical adenocarcinoma Homo sapiens CVCL_0030
Response regulation USP11 is highly expressed in patients with non-small cell lung cancer (NSCLC) and positively correlated with NRF2 expression. Together, USP11 stabilizes NRF2 and is thus an important player in cell proliferation and ferroptosis.
Beclin-1 (BECN1) [Driver]
 Target Info 
In total 1 item(s) under this target
Experiment 1 Reporting the Ferroptosis Target of This Regulator [3]
Target for Ferroptosis Driver
Responsed Disease Spinal cord injury ICD-11: ND51
 Disease Info 
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Ubiquitin mediated proteolysis hsa04120
Autophagy hsa04140
Cell Process Cell ferroptosis
Cell autophagy
In Vitro Model
 HEK-293T cells Normal Homo sapiens CVCL_0063
In Vivo Model
The mouse SCIRI model was established in 6- to 8-week-old C57BL/6 male mice. Mice were anesthetized by isoflurane inhalation and fixed in a supine position, and a midline abdominal incision method was used. After positioning of the left kidney through the peritoneum, we carefully searched for and separated the abdominal aorta along the left renal artery. The abdominal aorta was clamped under the exit of the left renal artery (which was not clamped in sham-operated mice). After 60 min, the aneurysm clip was removed and blood perfusion was restored. After the operation, the mice were placed in a cage alone and kept warm, and the bladder was massaged once every 8 h until the bladder reflex was restored.

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Response regulation USP11 plays a key role in regulating ferroptosis and additionally identifies USP11-mediated autophagy-dependent ferroptosis as a promising target for the treatment of spinal cord ischemia-reperfusion injury (SCIRI). USP11 promotes autophagy activation by stabilizing Beclin 1, thereby leading to ferroptosis.
Unspecific Target [Unspecific Target]
In total 1 item(s) under this target
Experiment 1 Reporting the Ferroptosis Target of This Regulator [4]
Responsed Disease Intervertebral disc degeneration ICD-11: FA80
 Disease Info 
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Ubiquitin mediated proteolysis hsa04120
Cell Process Cell ferroptosis
In Vitro Model
 HEK-293T cells Normal Homo sapiens CVCL_0063
HNP (Human nucleus pulposus cells)
In Vivo Model
8-10 weeks old male mice were placed in prone position and anesthetized with isoflurane inhalation. The 1.5 cm-long longitudinal incision was made in 2 mm from the posterior midline. The superior and inferior articular processes, supraspinous ligament and interspinous ligament of the L4-L5 lumbar vertebrae were removed to construct LSI, which would induce IVDD. After the operation, the mice were placed in a warm environment.

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Response regulation Overexpression of USP11 significantly ameliorate oxidative stress-induced ferroptosis, thus relieving intervertebral disc degeneration (IVDD) by increasing Sirt3. Moreover, knockout of USP11 in vivo (USP11) resulted in exacerbated IVDD and poor pain-related behavioral scores, which could be reversed by overexpression of Sirt3 in intervertebral disc.
Lung cancer [ICD-11: 2C25]
 Disease Info 
In total 2 item(s) under this disease
Experiment 1 Reporting the Ferroptosis-centered Disease Response [1]
Target Regulator Ubiquitin carboxyl-terminal hydrolase 11 (USP11) Protein coding
 Regulator Info 
Responsed Drug RSL3 Investigative
 Drug Info 
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Ubiquitin mediated proteolysis hsa04120
Cell Process Cell ferroptosis
In Vitro Model
 A-549 cells Lung adenocarcinoma Homo sapiens CVCL_0023
H2122 cells Lung adenocarcinoma Homo sapiens CVCL_1531
In Vivo Model
After two weeks in house, the mice were subcutaneously injected with A549 cells (100 uL containing 5 x 106 cells/injection) and monitored for tumor cell xenografts to reach approximately 100 mm3. The mice were then divided into two groups (n = 5), the RSL3 treatment (100 mg/kg; dissolved in 5% dimethyl sulfoxide/corn oil; administrated intratumorally twice a day for one week) and control (5% dimethyl sulfoxide/corn oil only) groups.

    Click to Show/Hide
Response regulation RSL3 was able to directly bind to USP11, a recently identified de-ubiquitinase of NRF2, and inactivate USP11 protein to induce NRF2 protein ubiquitination and degradation in KLK lung adenocarcinoma cells.
Experiment 2 Reporting the Ferroptosis-centered Disease Response [2]
Target Regulator Ubiquitin carboxyl-terminal hydrolase 11 (USP11) Protein coding
 Regulator Info 
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Ubiquitin mediated proteolysis hsa04120
Cell Process Cell ferroptosis
Cell proliferation
In Vitro Model
 HEK-293T cells Normal Homo sapiens CVCL_0063
NCI-H1299 cells Lung large cell carcinoma Homo sapiens CVCL_0060
HCT 116 cells Colon carcinoma Homo sapiens CVCL_0291
A-549 cells Lung adenocarcinoma Homo sapiens CVCL_0023
HeLa cells Endocervical adenocarcinoma Homo sapiens CVCL_0030
Response regulation USP11 is highly expressed in patients with non-small cell lung cancer (NSCLC) and positively correlated with NRF2 expression. Together, USP11 stabilizes NRF2 and is thus an important player in cell proliferation and ferroptosis.
Spinal cord injury [ICD-11: ND51]
 Disease Info 
In total 1 item(s) under this disease
Experiment 1 Reporting the Ferroptosis-centered Disease Response [3]
Target Regulator Ubiquitin carboxyl-terminal hydrolase 11 (USP11) Protein coding
 Regulator Info 
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Ubiquitin mediated proteolysis hsa04120
Autophagy hsa04140
Cell Process Cell ferroptosis
Cell autophagy
In Vitro Model
 HEK-293T cells Normal Homo sapiens CVCL_0063
In Vivo Model
The mouse SCIRI model was established in 6- to 8-week-old C57BL/6 male mice. Mice were anesthetized by isoflurane inhalation and fixed in a supine position, and a midline abdominal incision method was used. After positioning of the left kidney through the peritoneum, we carefully searched for and separated the abdominal aorta along the left renal artery. The abdominal aorta was clamped under the exit of the left renal artery (which was not clamped in sham-operated mice). After 60 min, the aneurysm clip was removed and blood perfusion was restored. After the operation, the mice were placed in a cage alone and kept warm, and the bladder was massaged once every 8 h until the bladder reflex was restored.

    Click to Show/Hide
Response regulation USP11 plays a key role in regulating ferroptosis and additionally identifies USP11-mediated autophagy-dependent ferroptosis as a promising target for the treatment of spinal cord ischemia-reperfusion injury (SCIRI). USP11 promotes autophagy activation by stabilizing Beclin 1, thereby leading to ferroptosis.
Intervertebral disc degeneration [ICD-11: FA80]
 Disease Info 
In total 1 item(s) under this disease
Experiment 1 Reporting the Ferroptosis-centered Disease Response [4]
Target Regulator Ubiquitin carboxyl-terminal hydrolase 11 (USP11) Protein coding
 Regulator Info 
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Ubiquitin mediated proteolysis hsa04120
Cell Process Cell ferroptosis
In Vitro Model
 HEK-293T cells Normal Homo sapiens CVCL_0063
HNP (Human nucleus pulposus cells)
In Vivo Model
8-10 weeks old male mice were placed in prone position and anesthetized with isoflurane inhalation. The 1.5 cm-long longitudinal incision was made in 2 mm from the posterior midline. The superior and inferior articular processes, supraspinous ligament and interspinous ligament of the L4-L5 lumbar vertebrae were removed to construct LSI, which would induce IVDD. After the operation, the mice were placed in a warm environment.

    Click to Show/Hide
Response regulation Overexpression of USP11 significantly ameliorate oxidative stress-induced ferroptosis, thus relieving intervertebral disc degeneration (IVDD) by increasing Sirt3. Moreover, knockout of USP11 in vivo (USP11) resulted in exacerbated IVDD and poor pain-related behavioral scores, which could be reversed by overexpression of Sirt3 in intervertebral disc.
RSL3 [Investigative]
 Drug Info 
In total 1 item(s) under this drug
Experiment 1 Reporting the Ferroptosis-centered Drug Response [1]
Drug for Ferroptosis Inducer
Response Target Nuclear factor erythroid 2-related factor 2 (NFE2L2) Suppressor; Marker
 Target Info 
Responsed Disease Lung cancer ICD-11: 2C25
 Disease Info 
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Ubiquitin mediated proteolysis hsa04120
Cell Process Cell ferroptosis
In Vitro Model
 A-549 cells Lung adenocarcinoma Homo sapiens CVCL_0023
H2122 cells Lung adenocarcinoma Homo sapiens CVCL_1531
In Vivo Model
After two weeks in house, the mice were subcutaneously injected with A549 cells (100 uL containing 5 x 106 cells/injection) and monitored for tumor cell xenografts to reach approximately 100 mm3. The mice were then divided into two groups (n = 5), the RSL3 treatment (100 mg/kg; dissolved in 5% dimethyl sulfoxide/corn oil; administrated intratumorally twice a day for one week) and control (5% dimethyl sulfoxide/corn oil only) groups.

    Click to Show/Hide
Response regulation RSL3 was able to directly bind to USP11, a recently identified de-ubiquitinase of NRF2, and inactivate USP11 protein to induce NRF2 protein ubiquitination and degradation in KLK lung adenocarcinoma cells.
References
Ref 1 The RSL3 Induction of KLK Lung Adenocarcinoma Cell Ferroptosis by Inhibition of USP11 Activity and the NRF2-GSH Axis. Cancers (Basel). 2022 Oct 25;14(21):5233. doi: 10.3390/cancers14215233.
Ref 2 The deubiquitinase USP11 regulates cell proliferation and ferroptotic cell death via stabilization of NRF2 USP11 deubiquitinates and stabilizes NRF2. Oncogene. 2021 Mar;40(9):1706-1720. doi: 10.1038/s41388-021-01660-5. Epub 2021 Feb 2.
Ref 3 USP11 regulates autophagy-dependent ferroptosis after spinal cord ischemia-reperfusion injury by deubiquitinating Beclin 1. Cell Death Differ. 2022 Jun;29(6):1164-1175. doi: 10.1038/s41418-021-00907-8. Epub 2021 Nov 27.
Ref 4 The deubiquitinase USP11 ameliorates intervertebral disc degeneration by regulating oxidative stress-induced ferroptosis via deubiquitinating and stabilizing Sirt3. Redox Biol. 2023 Jun;62:102707. doi: 10.1016/j.redox.2023.102707. Epub 2023 Apr 20.